Shawkat A. Abdel-Mohsen

Cancer is a complex and heterogeneous disease and is still one of the leading causes of morbidity and mortality worldwide, mostly as the population ages. Despite the encouraging advances made over the years in chemotherapy, the development of new compounds for cancer treatments is an urgent priority. In recent years, the design and chemical synthesis of several innovative hybrid molecules, which bring different pharmacophores on the same scaffold, have attracted the interest of many researchers. Following this strategy, we designed and synthetized a series of new hybrid compounds that contain three pharmacophores, namely trimethoxybenzene, thiazolidinedione and thiazole, and tested their anticancer properties on two breast cancer (MCF-7 and MDA-MB-231) cell lines and one melanoma (A2058) cell line. The most active compounds were particularly effective against the MCF-7 cells and did not affect the viability of the normal MCF-10A cells. Docking simulations indicated the human Topoisomerases I and II (hTopos I and II) as possible targets of these compounds, the inhibitory activity of which was demonstrated by the mean of direct enzymatic assays. Particularly, compound 7e was proved to inhibit both the hTopo I and II, whereas compounds 7c,d blocked only the hTopo II. Finally, compound 7e was responsible for MCF-7 cell death by apoptosis. The reported results are promising for the further design and synthesis of other analogues potentially active as anticancer tools.

The synthesis of 5-acetyl-6-methyl-4-(1,3-diphenyl-1H-pyrazol-4-yl)-3,4-dihydropyrmidin-2(1H)-thione was achieved by one-pot three-component synthesis using CaCl₂ in refluxing EtOH. The starting compound was utilized to synthesize a new series of 5-pyrazolyl; isoxazolyl; pyrimidinyl derivatives via the synthesized chalcone. Also, fused isoxazolo [5,4-d]pyrimidine and pyrazolo[3,4-d]pyrimidine were obtained by the treatment of 5-acetyl derivative with hydroxyl amine and/ or hydrazine hydrate. Also, the thiosemicarbazide derivative was prepared and utilized to synthesize other new thiazole derivatives. The structures of all compounds have been established on the basis of their analytical and spectral data. All compounds was also evaluated for their antibacterial and antifungal activity against various strains of bacteria and fungi. Also, the anti-inflammatory activity of some of synthesized compounds was evaluated using the carrageenan induced paw oedema test in rats using indomethacin as the reference drug.